Iouzalen L, Stepien O, Marche P
Department of Pharmacology, CNRS URA 1482, University René Descartes, Necker Medical School, Paris, France.
J Pharmacol Exp Ther. 1999 Apr;289(1):181-7.
Angiotensin II (AII), an important hypertrophic factor in the cardiovascular system, exerts most of its known effects in vivo through the AII receptor type 1 (AT1) subclass of AII receptors. These receptors are also responsible for the growth-related effects of AII in cultured vascular smooth muscle cells (VSMCs). We presently investigated the effects of BAY 10-6734 (Embusartan), a new orally active AT1 antagonist, on VSMC growth and proliferation of cultured VSMCs isolated from the aortae of Wistar Kyoto rats and spontaneously hypertensive rats. BAY 10-6734 and losartan (considered as AT1 receptor antagonist of reference), as well as their respective active metabolites, were studied for their inhibition of: 1) [125I]AII binding to its receptors, 2) AII-induced DNA and protein synthesis (by measuring the incorporation of 5-bromo-2'-deoxyuridine and [3H]L-leucine, respectively), and 3) AII-induced variations in intracellular Ca2+ concentration, using cells labeled with Fura-2. All of the tested compounds inhibited the aforementioned parameters in a concentration-dependent manner. Half-maximal inhibitory concentration values indicated that BAY 10-6734 was significantly more potent than losartan and that spontaneously hypertensive rat-derived VSMCs were more sensitive than Wistar Kyoto rat-derived ones. Neither BAY 10-6734 nor losartan affected the intracellular Ca2+ concentration of unstimulated VSMCs but both compounds inhibited both AII-induced Ca2+ mobilization from internal stores and Ca2+ influx. Neither compound affected arginine-vasopressin-, basic fibroblast growth factor-, or serum-induced DNA and protein synthesis. BAY 10-6734 appears therefore as a potent and specific new inhibitor of AII-induced growth-related events in VSMCs.
血管紧张素II（AII）是心血管系统中一种重要的肥大因子，它在体内的大部分已知作用是通过AII受体的1型（AT1）亚类介导的。这些受体也介导了AII在培养的血管平滑肌细胞（VSMC）中与生长相关的作用。我们目前研究了新型口服活性AT1拮抗剂BAY 10 - 6734（依布沙坦）对从Wistar Kyoto大鼠和自发性高血压大鼠主动脉分离的培养VSMC生长和增殖的影响。研究了BAY 10 - 6734和氯沙坦（被视为参考AT1受体拮抗剂）及其各自的活性代谢产物对以下方面的抑制作用：1）[125I]AII与其受体的结合；2）AII诱导的DNA和蛋白质合成（分别通过测量5 - 溴 - 2'-脱氧尿苷和[3H]L - 亮氨酸的掺入量）；3）使用Fura - 2标记的细胞，检测AII诱导的细胞内Ca2 +浓度变化。所有测试化合物均以浓度依赖性方式抑制上述参数。半数最大抑制浓度值表明，BAY 10 - 6734比氯沙坦的效力显著更强，并且源自自发性高血压大鼠的VSMC比源自Wistar Kyoto大鼠的VSMC更敏感。BAY 10 - 6734和氯沙坦均不影响未受刺激的VSMC的细胞内Ca2 +浓度，但两种化合物均抑制AII诱导的细胞内钙库释放Ca2 +以及Ca2 +内流。两种化合物均不影响精氨酸加压素、碱性成纤维细胞生长因子或血清诱导的DNA和蛋白质合成。因此，BAY 10 - 6734似乎是一种强效且特异性的新型抑制剂，可抑制AII诱导的VSMC中与生长相关的事件。
